REGU®-FADEThe most effective solution for noticeably brighter skin

© 2013 DSM Nutritional Products, 4002 Basel, Switzerland. www.dsm.com/personal-careAll rights reserved. No part of this brochure may be reproduced, distributed or translated in any form or by any means, or stored in a database or retrieval system, without the prior written permission of DSM Nutritional Products AG (“DSM”). While making reasonable efforts to ensure that all information in this brochure is accurate and up to date, DSM makes no representation or warranty of the accuracy, reliability, or completeness of the information. Use of this information shall be at your discretion and risk. Nothing herein relieves you from carrying out your own suitability determinations and tests and from your obligation to comply with all applicable laws and regulations and to observe all third party rights. The uses and claims for DSM’s products recommended in the brochure should be adapted to the current local regulatory environment. We disclaim any and all liability in connection with your product or its use.

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EuropeDSM Nutritional Products Europe Ltd.P.O. Box 2676, 4002 BaselSwitzerlandPhone: +41 61 815 7777Fax: +41 61 815 7860Email: info.pc-emea@dsm.com

Asia PacificDSM Nutritional Products Asia Pacific2 Havelock Road #04-01 Singapore 059763 Phone: +65 6632 6617Fax: +65 6632 6600 Email: info.pc-apac@dsm.com

North AmericaDSM Nutritional Products, LLC45 Waterview Boulevard, Parsippany, NJ 07054United States of AmericaPhone: +1 800 526 0189Fax: +1 973 257 8580Email: info.pc-na@dsm.com

Latin AmericaDSM Productos Nutricionais Brasil Ltda. Av. Engº Billings, 1729 Prédio 31 Jaguaré – São Paulo – SP – Brasil 05321-010Phone: + 55 11 3760 6409Fax: + 55 11 3760 6492Email: info.pc-latam@dsm.com

1 | α-MSH signalling REGU®-FADE downregulates the MCR1 (α-MSH receptor) expression level to 49% in melanocytes, leading to decreased expression of MITF-related genes such as TYR (tyrosinase), TRP1, DCT, SILV and OCA2 which reduces melanin synthesis.

2 | KIT signalling REGU®-FADE decreases KIT (=stem cell factor receptor) gene expression to 58% in melanocytes which additionally reduces melanin synthesis.

3 | Melanosome function and maturation REGU®-FADE also affects the function and maturation of melanosomes by reducing SLC24A5 (-39%) and SLC45A2 (-74%) gene expression levels.

4 | Melanosome transport REGU®-FADE attenuates melanosome transport within melanocytes, shown by the reduction of the MYO5A (-55 %) and MREG (-69 %) gene expression levels, as well as melanosome transport to keratinocytes, shown by the reduction of RAB 27A (-24%) gene expression levels.

5 | Melanin synthesis REGU®-FADE reduces the conversion of tyrosine into eumelanin or pheomelanin at various points, shown by the downregulation of OCA2 (-37%), TYR (tyrosinase) (-31%), DCT (-85%) and TRP1 (-63%) gene expression levels.

α-MSH

Adenylatecyclase

MC1R

cAMP CREB

MITF gene

MITF

MAPK

SCFKit

MITF

MITF

MelanogenicEnzyme

Expression MITFdegradation

Melanosome

DCT

OCA2

SILVTYR

TRP1SLC45A2

SLC24A5RAB27A

Melanocyte

Keratinocyte

MYO5A

MREG

1.

2.

3.

4.

5.

Effect of REGU-FADE: reduced expression

Skin brightening is one of the fastest growing segments in the cosmetic industry. In Asia skin brighteners are widely used to make skin fairer. In Western countries consumers want to diminish age spots, reduce excessive pigmentation and achieve an even skin tone. As a consequence, these markets are looking for increasingly efficient, fast-acting skin brighteners. At the same time, these actives must be absolutely safe for cosmetic use.

REGU®-FADE is high-performing and fast-acting. It uses pure nature-identical trans-reservatrol that is free from pesticides and emodin, addressing high consumer awareness about safety and visible effects. Resveratrol is a known potent antioxidant found in red grapes and associated with various health benefits.

REGU®-FADE has proven its outstanding efficacy in human clinical trials with visible effects in only 2 weeks. Compared with a market benchmark, REGU®-FADE worked faster early on and reduced the production of melanin more effectively throughout the studies. DSM scientists showed that REGU®-FADE attenuates skin pigmentation via multiple mechanisms, from initial signaling and gene expression to melanin production and final melanosome transfer.

In vitroMelanin assay on B16F10 cells Low concentration REGU®-FADE (0.001%) leads to a 50% reduction of melanin content.

Melanin assay on normal human melanocytes REGU®-FADE (0.0014%) decreases melanin production with higher activity than kojic acid.

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Melanin Biosynthesis Melano-genesis

TYRP1 DCT MC1RBr

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T

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Tissue: Human Melanocytes

Tissue: 88µM REGU®-FADE 118µM AscHlc

Timepoint: 72 hours

3°

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Days

* p ≤ 0.05 vs. vehicle

* p ≤ 0.05 vs. vehicle60 80

∆ IT

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REGU®-FADE 1%

REGU®-FADE 0.2%

Ascorbyl glucoside 2%

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0Vehicle Ascorbyl glucoside 2% REGU®-FADE 1%

∆ IT

A°

100%

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0Control 100 µM PTU 44 µM

NEGATIVECONTROL

REGU®-FADEKojic acid

EC50=~60µM0.0014%

EC50=~100µM

POSITIVECONTROL

REGU®-FADE(0.001%)

% m

elan

in p

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Melanin Biosynthesis Melano-genesis

TYRP1 DCT MC1R

Brig

hten

ing

Tan

ning

Tissue: Human Melanocytes

Tissue: 88µM REGU®-FADE 118µM AscHlc

Timepoint: 72 hours

3°

2°

1°

00 20 40

Days

* p ≤ 0.05 vs. vehicle

* p ≤ 0.05 vs. vehicle60 80

∆ IT

A°

Dark

er s

kin

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ter s

kin

Vehicle

REGU®-FADE 1%

REGU®-FADE 0.2%

Ascorbyl glucoside 2%

8°

6°

4°

2°

0Vehicle Ascorbyl glucoside 2% REGU®-FADE 1%

∆ IT

A°

100%

80%

60%

40%

20%

0Control 100 µM PTU 44 µM

NEGATIVECONTROL

REGU®-FADEKojic acid

EC50=~60µM0.0014%

EC50=~100µM

POSITIVECONTROL

REGU®-FADE(0.001%)

% m

elan

in p

rodu

ctio

n

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ours

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72 h

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In vivoLong-term study A double-blind, placebo-controlled study was performed on 52 Indian female volunteers. Per test area a cream (SPF ~10) plus test substance was applied twice daily on the forearms. Colorimetric measurements were performed after 14, 28, 60 and 90 days respectively.

Significant skin brightening with 1% REGU®-FADE

Short-term study A double-blind, placebo-controlled study was performed on 12 Caucasian volunteers. Per test area creams were applied 3 times per day on the forearm. Colorimetric measurements were performed after 14 days.

Visible and significant skin brightening in 2 weeks with 1% REGU®-FADE

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-100SILV OCA2 TYR

Melanin Biosynthesis Melano-genesis

TYRP1 DCT MC1R

Brig

hten

ing

Tan

ning

Tissue: Human Melanocytes

Tissue: 88µM REGU®-FADE 118µM AscHlc

Timepoint: 72 hours

3°

2°

1°

00 20 40

Days

* p ≤ 0.05 vs. vehicle

* p ≤ 0.05 vs. vehicle60 80

∆ IT

A°

Dark

er s

kin

Ligh

ter s

kin

Vehicle

REGU®-FADE 1%

REGU®-FADE 0.2%

Ascorbyl glucoside 2%

8°

6°

4°

2°

0Vehicle Ascorbyl glucoside 2% REGU®-FADE 1%

∆ IT

A°

100%

80%

60%

40%

20%

0Control 100 µM PTU 44 µM

NEGATIVECONTROL

REGU®-FADEKojic acid

EC50=~60µM0.0014%

EC50=~100µM

POSITIVECONTROL

REGU®-FADE(0.001%)

% m

elan

in p

rodu

ctio

n

24 h

ours

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-100SILV OCA2 TYR

Melanin Biosynthesis Melano-genesis

TYRP1 DCT MC1R

Brig

hten

ing

Tan

ning

Tissue: Human Melanocytes

Tissue: 88µM REGU®-FADE 118µM AscHlc

Timepoint: 72 hours

3°

2°

1°

00 20 40

Days

* p ≤ 0.05 vs. vehicle

* p ≤ 0.05 vs. vehicle60 80

∆ IT

A°

Dark

er s

kin

Ligh

ter s

kin

Vehicle

REGU®-FADE 1%

REGU®-FADE 0.2%

Ascorbyl glucoside 2%

8°

6°

4°

2°

0Vehicle Ascorbyl glucoside 2% REGU®-FADE 1%

∆ IT

A°

100%

80%

60%

40%

20%

0Control 100 µM PTU 44 µM

NEGATIVECONTROL

REGU®-FADEKojic acid

EC50=~60µM0.0014%

EC50=~100µM

POSITIVECONTROL

REGU®-FADE(0.001%)

% m

elan

in p

rodu

ctio

n

24 h

ours

48 h

ours

72 h

ours

24 h

ours

48 h

ours

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48 h

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ours

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log c (substance) [µM]

% m

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EfficacyA growing segment

Skin pigmentation involves many genes at various steps. A gene expression test (RT-PCR) has been performed and showed that REGU®-FADE (0.002%) is very effective in attenuating the melanin production cascade at multiple points.

Mechanism

Key facts

Benefits

•Visiblybrighterskinin2weeks

•Natureidenticalpuretrans-resveratrolformoreeffective and even skin brightening

•Multi-targetmechanism

Cosmetic application

•Skinbrighteningfacialandbodycareproducts

•Creamsandserumsforagespots

•Anti-agingskincareproductsformoreevenskintone

Suggested concentration

•Upto1%REGU®-FADE in cosmetic formulations

INCI name

Resveratrol

Structure

• trans-Resveratrol(molecularweight:228.25g/mol)